Received: March Accepted after revision: April First published online: May

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1 Correspondence: Mathieu S. Bolhuis, University of Groningen, University Medical Centre Groningen, Dept of Clinical Pharmacy and Pharmacology, University of Groningen, PO Box , 9700 RB Groningen, The Netherlands. Received: March Accepted after revision: April First published online: May Conflict of interest: Disclosures can be found alongside the online version of this article at erj.ersjournals.com References 1 Falzon D, Jaramillo E, Schunemann HJ, et al. WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update. Eur Respir J 2011; 38: De Lorenzo S, Alffenaar JW, Sotgiu G, et al. Efficacy and safety of meropenem clavulanate added to linezolidcontaining regimens in the treatment of MDR-/XDR-TB. Eur Respir J 2013; 41: Migliori GB, Eker B, Richardson MD, et al. A retrospective TBNET assessment of linezolid safety, tolerability and efficacy in multidrug-resistant tuberculosis. Eur Respir J 2009; 34: Sotgiu G, Centis R, D Ambrosio L, et al. Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis. Eur Respir J 2012; 40: Lee M, Lee J, Carroll MW, et al. Linezolid for treatment of chronic extensively drug-resistant tuberculosis. N Engl J Med 2012; 367: Truffot-Pernot C, Lounis N, Grosset JH, et al. Clarithromycin is inactive against Mycobacterium tuberculosis. Antimicrob Agents Chemother 1995; 39: Honeybourne D, Kees F, Andrews JM, et al. The levels of clarithromycin and its 14-hydroxy metabolite in the lung. Eur Respir J 1994; 7: Cavalieri SJ, Biehle JR, Sanders WE Jr. Synergistic activities of clarithromycin and antituberculous drugs against multidrug-resistant Mycobacterium tuberculosis. Antimicrob Agents Chemother 1995; 39: van Klingeren B, Dessens-Kroon M, van der Laan T, et al. Drug susceptibility testing of Mycobacterium tuberculosis complex by use of a high-throughput, reproducible, absolute concentration method. J Clin Microbiol 2007; 45: Alffenaar JW, van der Laan T, Simons S, et al. Susceptibility of clinical Mycobacterium tuberculosis isolates to a potentially less toxic derivate of linezolid, PNU Antimicrob Agents Chemother 2011; 55: Odds FC. Synergy, antagonism, and what the chequerboard puts between them. J Antimicrob Chemother 2003; 52: Bolhuis MS, Altena RV, Soolingen DV, et al. Clarithromycin increases linezolid exposure in multidrug-resistant tuberculosis patients. Eur Respir J 2013; 42: Srivastava S, Peloquin CA, Sotgiu G, et al. Therapeutic drug management: is it the future of multidrug-resistant tuberculosis treatment? Eur Respir J 2013; 42: Diel R, Loddenkemper R, Zellweger JP, et al. Old ideas to innovate tuberculosis control: preventive treatment to achieve elimination. Eur Respir J 2013; 42: D Ambrosio L, Dara M, Tadolini M, et al. Tuberculosis elimination: theory and practice in Europe, Eur Respir J 2014; 43: Eur Respir J 2014; 44: DOI: / Copyright ßERS 2014 ERS/WHO Tuberculosis Consilium assistance with extensively drug-resistant tuberculosis management in a child: case study of compassionate delamanid use To the Editor: The European Respiratory Society (ERS) and the World Health Organization (WHO) Regional Office for Europe implemented a consultation body, the ERS/WHO Tuberculosis (TB) Consilium, in late April 2013 [1 4]. This is a novel, high-priority initiative, as part of the Presidential plan, to face the growing problem of drug-resistant TB in Europe and globally to support clinicians in managing difficult-to-treat TB cases. Clinicians are increasingly challenged by difficult-to-treat cases of multidrug-resistant (MDR)-TB (i.e. TB caused by Mycobacterium tuberculosis strains resistant to isoniazid and rifampicin) and extensively drug-resistant (XDR)-TB (i.e. TB caused by MDR-TB strains that are also resistant to at least one fluoroquinolone and one injectable second-line anti-tb drug) [5 8]. MDR/XDR-TB is seriously hampering TB control and elimination in Europe [9 11], as patients require long and expensive regimens with significant adverse effects, while cure rates remain low [7, 8, 12 14]. 811

2 Clinicians can upload a case description and queries via the ERS/WHO TB Consilium website (www. tbconsilium.org), the process of which takes up to 20 minutes. The case is then assigned to global experts who provide feedback to the clinician s questions in a limited timeframe, free of charge. At the time of writing, the TB Consilium has provided expert opinion on 51 cases (and two outbreaks from 11 countries), with an average response time of 36 h. The most frequently posed questions are related to the design and duration of the most appropriate regimens for difficult-to-treat patients [4]. In the absence of a sufficient number of medicines to which a strain is sensitive in vivo, life-saving treatment may rely on the use of new medicines (bedaquiline or delamanid) either under conditional or through compassionate use [15 18]. We describe the contribution of the TB Consilium e-platform to the management of the first case accessing delamanid for compassionate use, with an overview of the epidemic context. The patient (male; 12 years old; native Italian; no comorbidities or risk factors for TB) was diagnosed in October 2013 in Milan (Italy) with both laryngeal and pulmonary TB. The patient reported progressive dysphonia, including aphonia, associated with hearing loss of the right ear as well as asthenia and weakness since May A chest radiograph showed multiple nodular infiltrates in both lungs with fibrotic and calcified areas suggestive of pulmonary TB. A tuberculin skin test (TST) was negative but an interferon-c release assay (IGRA) (QuantiFERON Gold; Qiagen GmbH, Hilden, Germany) was positive. Direct gastric aspirate smear microscopy for acid-fast bacilli was positive as was gastric aspirate culture for M. tuberculosis. The M. tuberculosis isolate (Haarlem strain) was resistant to all first-line drugs, as well as ethionamide, the fluoroquinolones and all injectable agents. Based on early detection of rifampicin resistance by Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA) the patient was initially prescribed (October 4) ethambutol, pyrazinamide, high-dose isoniazid and moxifloxacin. On October 30, when complete drug susceptibility test (DST) results became available (showing resistance to all first- and second-line drugs except para-aminosalicylic acids (PAS) and linezolid), the regimen was re-designed (fig. 1). Following clinical and radiological (chest radiography and computed tomography (CT)) improvement, and bacteriological conversion of the gastric aspirate smear microscopy (the culture remaining positive), the patient was discharged on December 12. Despite good treatment adherence, on January 27, 2014, direct smear aspirates reverted to positive (the culture remaining positive) and the patient experienced progressive clinical deterioration with loss of 4 kg body weight (down to 37.9 kg from 42 kg at discharge). His haemoglobin decreased from 11 g?dl -1 to 8.5 g?dl -1. The patient was re-hospitalised on February 2 and the treatment regimen modified, with further adjustment on February 9 (fig. 1). The patient received a blood transfusion and parenteral nutrition was started. In order to select the most appropriate treatment regimen for the young patient, the TB Consilium platform was used and four different world experts in paediatric MDR/XDR-TB management were consulted. All of them recommended inclusion of one of the newly approved TB drugs (either bedaquiline or delamanid; not both, because of lack of safety data with concomitant use or the drug drug interaction) in a regimen that included meropenem and clofazimine. Following the experts recommendations, delamanid was procured in 10 days via the manufacturer (Otsuka Europe, Wrexham, UK) and treatment initiated on March 1, with close monitoring of the patient. The Consilium experts opinion played a crucial role in the manufacturer s decision to create a name-based compassionate programme for delamanid. Initial clinical, laboratory and radiological improvement was observed, including bacteriological conversion (gastric aspirate as well as smear and culture; provisional result at week 3). Contact screening revealed a complex pattern of infection and likely transmission. Within the household, the index case s sister (6 years old) and brother (10 years old) were diagnosed with smear- and culturenegative TB (from gastric aspirates) with pathological images on CT. They were prescribed a regimen including isoniazid, pyrazinamide, moxifloxacin and linezolid from October, remaining symptom free. The mother had latent TB infection (LTBI), being TST and IGRA (QuantiFERON) positive, whereas the father was negative for both tests. Investigations of the index case s school-related contacts identified two schoolmates affected by TB. A girl born in Morocco had sputum-negative pulmonary TB (negative culture from bronchoalveolar lavage but positive histology from hilar lymph node biopsy). She completed 6 months of the standard first-line regimen with a good treatment response. A second case, a boy born in Romania, had monolateral pleurisy with modest symptoms, reflecting recent infection (most likely by the index case). He was prescribed the same regimen as the index case (moxifloxacin, amoxicillin-clavulanate, terizidone, clarithromycin, linezolid 812

3 a) TB disease TST +, QF + TST +, QF - Male 12 years old Laryngeal + PTB Long diagnostic delay Direct sputum examination Resistant to SHREZ+FQ+Inj+Eto Haarlem strain Index case School Family Other circles Sister, 6 years old, PTB Brother, 10 years old, PTB Mother, TST +, QF + Father, TST -, QF - PTB, foreign born, histopathology + CXR improved cat 1 21 classmates tested: 1 monolateral pleurisy (foreign born) 10 TST +, QF + (7 native, 3 foreign born) 24 students tested in parallel class performing common activities: 1 TST +, QF - 57 students tested in other classes: 13 TST +, QF - 18 school staff tested: 4 TST +, QF + 5 TST +, QF - 19 school canteen staff tested: 3 TST +, QF + Sport-related circle 27 tested: All TST -, QF - Summer camp circle 56 playmates tested: 3 TST +, QF - (BCG vaccinated) 37 educators tested: 1 TST +, QF - Catechism-related circle 50 tested: 4 TST +, QF - Other contacts: 2 dental hygienists tested: 2 TST +, QF + b) Delamanid Ethionamide Clofazimine Amikacin Meropenem PAS Linezolid Clarithromycin Terizidone Amox/Clv Moxifloxacin Isoniazid Pyrazinamide Ethambutol 1/03 28/03 9/02 10/03 28/03 9/02 05/03 28/03 9/02 9/02 1/03 28/03 7/11 7/03 28/03 1/03 28/03 1/03 28/03 9/02 October 2013 November 2013 December 2013 January 2014 February 2014 March 2014 FIGURE 1 a) Evaluation of the Milan extensively drug-resistant tuberculosis epidemic (2013) managed through the European Respiratory Society/World Health Organization Consilium s expert advice and b) summary of drugs included in the treatment regimen of the index case. Numbers in b) represent date/month. The dosages were as follows. October 4, 2013 (start): ethambutol 400 mg twice daily p.o., pyrazinamide 700 mg twice daily p.o., high-dose isoniazid 400 mg twice daily p.o. and moxifloxacin 550 mg once daily p.o. October 30, 2013 (complete drug susceptibility test available): moxifloxacin 550 mg once daily p.o., amoxicillin-clavulanate (Amox/Clv) 1 g three times per day i.v., terizidone 750 mg once daily p.o., clarithromycin 300 mg twice daily p.o. and linezolid 600 mg twice daily i.v.; linezolid and Amox/Clv were administered i.v. for 6 weeks and then were given orally at the same dosage. November 7, 2013: para-aminosalicylic acid (PAS) 6 g once daily p.o. was added. February 2, 2014: Amox/Clv 1 g three times per day i.v., linezolid 600 mg twice daily i.v., oral moxifloxacin 550 mg once daily p.o., terizidone 750 mg once daily p.o., clarithromycin 300 mg twice daily p.o. and PAS 6 g once daily p.o. February 9, 2014: clofazimine 200 mg once daily p.o. and ethionamide 750 mg once daily p.o. were added, the treatment including linezolid 600 mg twice daily i.v., meropenem 1 g three times per day i.v., amikacin 750 mg OD i.v., Amox/Clv 1 g three times per day i.v., moxifloxacin 550 mg once daily p.o., PAS 550 mg once daily p.o. and high-dose isoniazid 400 mg twice daily p.o. February 19, 2014: all the drugs were stopped due to acute pancreatic insufficiency. March 1, 2014: delamanid 100 mg twice daily p.o. was added with linezolid 300 mg twice daily i.v., meropenem 1 g three times per day i.v. and Amox/Clv 700 g three times per day i.v. March 5, 2014: clofazimine 100 mg once daily p.o. was added to the regimen. March 7, 2014: PAS 8 g once daily p.o. was added to the regimen. March 10, 2014: ethionamide 500 mg once daily p.o. was added to the regimen. PTB: pulmonary tuberculosis; SHREZ+FQ+Inj+Eto: streptomycin, isoniazid, rifampicin and ethambutol, plus fluoroquinolone, all second-line injectables (amikacin, kanamycin and capreomycin) and ethionamide; TST: tuberculin skin test; QF: QuantiFERON; CXR: chest radiography; cat: category; BCG: bacille Calmette Guérin. 813

4 and PAS) and was improving clinically and radiologically at the time of writing. In addition, four members of the school staff, 10 schoolmates (seven native and three foreign born), two other students and another three individuals in the index case s other circles were found to have LTBI (QuantiFERON positive with no signs of TB). All LTBI individuals were undergoing clinical and radiological follow-up at the time of writing. This is the first report on the compassionate use of delamanid involving a paediatric XDR-TB case. The TB Consilium platform is a functional instrument to rapidly provide (24 h) four expert opinions on how best to manage a complex case. The Consilium s recommendations facilitated the delamanid manufacturer s decision to make the drug available for compassionate use in a child. On the basis of this positive experience, the manufacturer has proposed to use the TB Consilium as a tool to provide rapid clinical advice guiding the release of the compound for compassionate use. In the absence of a pre-existing national authorisation process for the compassionate use of an unregistered drug (formally approved in Europe for adults only) the TB Consilium experts opinion supported the treating team in obtaining clearance from Italian regulatory bodies (e.g. the hospital ethical committee and the National Drug Agency). This experience shows the importance of defining a specific, consensus-based roadmap to guide the rational and authorised use of the new TB drugs. It is essential to ensure rapid access to the new drugs in selected cases (to save patients lives and to break the transmission cycle), while the risk of cumulative resistance is minimised, and evidence about drug safety and effectiveness is collected. The Milan outbreak was further complicated by a second case that was probably infected by a different strain (it was not possible to identify the second strain). Overall, there were five cases with TB and 19 with LTBI (12 out of 19 in children). The epidemic required coordination of different clinical and public health units. It illustrates that TB elimination would be difficult in low-incidence countries if TB remains endemic in areas from where refugees and immigrants originate [9 11]. The TB Consilium platform, in addition to providing expert opinion in four different languages (English, Russian, Spanish and Portuguese) to clinicians and patients (the patient s version being in preparation at the time of writing) and to support cross-border case management, proved to be effective in supporting compassionate use of new drugs for MDR/XDR-TB Evaluation of the e-platform in assessing appropriateness of delamanid (compassionate use) in a complex XDR-TB case Susanna Esposito 1,10, Lia D Ambrosio 2,10, Marina Tadolini 3,10, H. Simon Schaaf 4, Josè Caminero Luna 5, Ben Marais 6, Rosella Centis 2, Masoud Dara 7, Alberto Matteelli 8, Francesco Blasi 9 and Giovanni Battista Migliori 2 1 Pediatric Highly Intensive Care Unit, Dept of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico, Milan, Italy. 2 World Health Organization Collaborating Centre for Tuberculosis and Lung Diseases, Fondazione S. Maugeri, Care and Research Institute, Tradate, Italy. 3 Section of Infectious Diseases, Dept of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy. 4 Desmond Tutu Tuberculosis Centre, Dept of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. 5 Dept of Pneumology, Hospital General de Gran Canaria, Las Palmas, Spain. 6 Marie Bashir Institute for Infectious Diseases and Biosecurity, and Children s Hospital at Westmead, Sydney Medical School, University of Sydney, Sydney, Australia. 7 World Health Organization Regional Office for Europe, Copenhagen, Denmark. 8 Institute of Infectious and Tropical Diseases, WHO Collaborating Centre for TB/HIV co-infection and TB elimination, University of Brescia, Brescia, Italy. 9 Dipartimento Fisiopatologia Medico-Chirurgica e dei Trapianti, University of Milan, IRCCS Fondazione Cà Granda, Milan, Italy. 10 These authors contributed equally. Correspondence: Giovanni Battista Migliori, World Health Organization Collaborating Centre for Tuberculosis and Lung Diseases, Fondazione S. Maugeri, Care and Research Institute, Via Roncaccio 16, 21049, Tradate, Italy. giovannibattista.migliori@fsm.it Received: March Accepted: April First published online: May Conflict of interest: None declared. Acknowledgements: The authors would like to acknowledge the following co-investigators: Luigi Ruffo Codecasa and Maurizio Ferrarese (Reference Center for TB, Lombardy Region, Milan, Italy); and Giorgio Ciconali and Marino Faccini (Prevention Dept, ASL Milano, Milan, Italy). The authors would also like to thank all those who participated in the management of the clinical case, as well as of the Milan outbreaks: Mario Raviglione (World Health Organization, Geneva, Switzerland); Maria Gramegna and Liliana Coppola (General Health Direction, Lombardy Region, Milan, Italy); Giorgio Ciconali and Marino Faccini (Prevention Dept, ASL Milano, Milan, Italy); Luigi Ruffo Codecasa (Reference Center for TB, Lombardy Region, Milan, Italy); Giovanni Pietro Gesu and Ester Mazzola (Laboratory Unit, Niguarda Hospital, Milan, Italy); Luigi Macchi, Anna Pavan, Pier Mannuccio Mannucci, Basilio Tiso, Francesca Venturini, Vito Ladisa, Samantha Bosis and Federica Massacesi (Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico, Milan, Italy); Daniela Cirillo (TB Supranational Reference laboratory, San Raffaele Scientific Institute, Milan, Italy); Stefano Vella (National Institute of Health, Rome, Italy); Giuseppe Ippolito and Francesco Lauria (IRCCS Spallanzani Hospital, Rome, 814

5 Italy); and Luca Pani and Maria Federica Barchetti (AIFA, Rome, Italy). Moreover, we would like to thank the Otsuka team (Otuska Europe, Wrexham, UK) for their efforts in supporting the management of this case. References 1 Blasi F, Dara M, van der Werf MJ, et al. Supporting TB clinicians managing difficult cases: the ERS/WHO Consilium. Eur Respir J 2013; 41: Blasi F, Barnes PJ, Gaga M, et al. Future Directions for the ERS: Presidential plans. Eur Respir J 2013; 42: World Health Organization. Global tuberculosis report Document WHO/HTM/TB/ Geneva, World Health Organization, D Ambrosio L, Tadolini M, Dupasquier S, et al. ERS/WHO TB Consilium: reporting of the initial 10 cases. Eur Respir J 2014; 43: Migliori GB, Dara M, de Colombani P, et al. Multidrug-resistant tuberculosis in Eastern Europe: still on the increase? Eur Respir J 2012; 39: Skrahina A, Hurevich H, Zalutskaya A, et al. Alarming levels of drug-resistant tuberculosis in Belarus: results of a survey in Minsk. Eur Respir J 2012; 39: Falzon D, Gandhi N, Migliori GB, et al. Resistance to fluoroquinolones and second-line injectable drugs: impact on multidrug-resistant TB outcomes. Eur Respir J 2013; 42: Migliori GB, Sotgiu G, Gandhi NR, et al. Drug resistance beyond extensively drug-resistant tuberculosis: individual patient data meta-analysis. Eur Respir J 2013; 42: Diel R, Loddenkemper R, Zellweger JP, et al. Old ideas to innovate tuberculosis control: preventive treatment to achieve elimination. Eur Respir J 2013; 42: D Ambrosio L, Dara M, Tadolini M, et al. TB elimination: theory and practice in Europe. Eur Respir J 2014; 43: Voniatis C, Migliori GB, Voniatis M, et al. Tuberculosis elimination, dream or reality? The case of Cyprus. Eur Respir J 2014; 44: Diel R, Rutz S, Castell S, et al. Tuberculosis: cost of illness in Germany. Eur Respir J 2012; 40: Falzon D, Jaramillo E, Schünemann HJ, et al. WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update. Eur Respir J 2011; 38: Migliori GB, Zellweger JP, Abubakar I, et al. European Union Standards for Tuberculosis Care. Eur Respir J 2012; 39: Diacon AH, Dawson R, von Groote-Bidlingmaier F, et al. The 14-day bactericidal activity of combinations of PA- 824, bedaquiline, pyrazinamide and moxifloxacin: the path to novel antituberculosis treatment regimens. Lancet 2012; 380: Tiberi S, De Lorenzo S, Centis R, et al. Bedaquiline in MDR-/XDR-TB cases: first experience on campassionate use. Eur Respir J 2014; 43: van Halsema C, Humphreys S, Bonington A. Extensively drug-resistant tuberculosis: early access to bedaquiline for a UK patient. Eur Respir J 2014; 43: Skripconoka V, Danilovits M, Pehme L, et al. Delamanid improves outcomes and reduces mortality for multidrugresistant tuberculosis. Eur Respir J 2013; 41: Eur Respir J 2014; 44: DOI: / Copyright ßERS